ABSTRACT Alcoholism carries significant personal and societal burdens, and yet we still lack effective treatments for alcohol use disorders. Several lines of research have demonstrated disruption of white matter (WM) in major tracts throughout the alcoholic brain. However, we know very little about how reward-related pathways are affected. Understanding the morphology of the alcoholic brain, particularly in projections to reward-related regions, is imperative to our understanding of the mechanisms that may underlie alcohol dependence and relapse. Therefore, our goal is to determine how WM structure of reward pathways relates to drinking behavior and neurochemical function (in particular, dopamine (DA), which is an important neurotransmitter in alcohol abuse and dependence). In order to achieve this goal, we will utilize a novel multi-modal neuroimaging approach by collecting both diffusion-weighted imaging (DWI) and dopaminergic positron emission tomography (PET) in the same subjects. Data from previous and ongoing NIH-funded studies will be analyzed, with final target samples of 91 nontreatment-seeking alcoholics (NTS) and 101 social drinkers (SD). DWI with tractography will be used to characterize the WM structure of reward pathways with cutting-edge connectomic metrics (e.g., number of fibers of a connection, fiber density), and variables from network-based algorithms (which give information about how efficient connections are between brain regions). Aim 1 will determine how connectomic and network metrics of reward-related WM pathways relate to drinking behaviors. Aim 2 will use a multimodal DWI/PET approach in order to determine how properties of reward-related WM projections (e.g., fractional anisotropy, connectomic indices, network efficiency) may differentially affect DA tone in NTS and SD. Specifically, we will test whether WM properties of cortico-striatal projections alter striatal DA tone (measured with [11C]raclopride) and whether thalamo-cortical WM tracts affect prefrontal cortical DA tone (measured with [18F]fallypride). The results of this study will greatly improve our understanding of how WM structure in reward pathways may contribute to alcoholism, and will facilitate future treatment development based on the relationships between brain structure, drinking behavior, and neurochemical function.